Gene-environment interaction is a seminal concept in molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer, and colon cancer, one of the cancer types associated with chronic inflammation. These studies require the integration of an increasing understanding of genetic variation in cancer susceptibility, analysis of carcinogen exposure, rapidly developing technologies, bioinformatics, social-ethical concerns, and epidemiological study-design methods. We have discovered that a deficient G2/M cell cycle checkpoint that responded to DNA damage, a phenotypic trait, is associated with a higher lung cancer risk in African-Americans than in Caucasians. Genotypic polymorphisms of certain inflammatory cytokine genes, e.g., IL-1a and IL-10, were also associated with lung cancer. We are continuing our longstanding studies of human lung carcinogenesis. The molecular profile of adenocarcinoma identified smoking- versus nonsmoking-associated cancers and short-term versus long-term survivors. We have also discovered molecular profiles of microRNAs, nonprotein coding genes that identify lung cancer, its different histological types and prognosis.